Randolph, JT; Lim, HB; Beyer, JM; Mondal, R; Panchal, NS; Colletti, L; Liu, Y; Koev, G; Kati, WM; Hernandez, LE; Beno, DWA; Krueger, AC; Longenecker, KL; Stewart, KD; Dumas, EO; Molla, A; Maring, CJ; Donner, PL; Pratt, JK; Liu, D; Motter, CE; Rockway, TW; Tufano, MD; Wagner, R; ,
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.